What is the source of self-reactive B cells in the periphery? We have demonstrated that inflammation influences early B cell development by inducing early emigration into the blood and peripheral lymphoid tissues. This mobilization is mediated by IL-1 and TNFa and is correlated with increases in the frequency of auto-reactive peripheral B cells. Some evidence suggests that auto-antibody responses, even those characterized by lg class-switched (CSR) and hypermutated (SHM) antibody may bypass the germinal center (GC) reaction. In humans and mice, AID expression is generally believed to be restricted to B cells within GC where lg somatic hypermutation (SHM) and class-switch recombination (CSR) are most active. In birds, rabbits, and sheep AID expression in fetal tissues diversifies the primary antibody repertoire by gene conversion and/or SHM in the absence of activation by exogenous antigens. Recently, we and others demonstrated that immature and transitional B cells in mice constitutively express AID. AID levels are low in these developmentally immature cells, but sufficient to drive CSR and SHM. We have now demonstrated similar levels of AID expression in human immature and transitional B cells, and most remarkably, in human fetal liver (FL). Indeed, the quantity of AID message (normalized to IgB) in FL is comparable to that of human tonsil, a tissue highly enriched for GC B cells. We shall investigate developmentally regulated AID expression in human pro-, pre-, and immature/transitional B cells to determine the consequences of early AID expression, and especially its role in the generation of auto-reactive, peripheral B lymphocytes. These experiments in normal subjects will be extended to patients with autoimmune disease and may reveal another pathway leading to mutated, self-reactive B cells that mature outside the normal boundaries of central tolerance.